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Objective Caspase-1 is required for nephritis and robust autoantibody development in the pristane model of murine lupus. The objective of this study was to evaluate the immune response and to study the splenic B and T cell populations in wild-type (WT) and caspase-1 -/- mice following pristane injection in order to develop an understanding of why absence of caspase-1 is protective in pristane-induced lupus. Methods Immunization responses to NP-Ficoll and NP-ovalbumin were assessed in WT and caspase-1 -/- mice. In vitro IgM and IgG responses to R848 were measured by ELISA. Serum IgM anti-dsDNA and IL-1β were also measured by ELISA. B and T cell populations 2 weeks and 6 months following pristane injection were measured by flow cytometry in WT and caspase-1 -/- mice. Results Caspase-1 -/- mice generate equivalent IgG responses to NP-Ficoll and NP-ova antigens when compared to wild-type mice. Additionally, they secrete IgM and IgG in response to TLR7 activation. Pristane injected WT and caspase-1 -/- mice generate robust IgM anti-dsDNA responses. Caspase-1 -/- mice have a significant reduction in marginal zone B cell populations compared to WT 6 months after pristane exposure whereas T cell responses are intact in these mice. Conclusions Caspase-1 -/- mice have intact immune responses but do not develop an expanded marginal zone B cell population in response to pristane-induced lupus. This may be one explanation for reduced IgG autoantibody production in these mice. [ABSTRACT FROM AUTHOR]

We improve on the known upper bound for the minimum weight of the dual codes of translation planes of certain orders by providing a general construction of words of small weight. We use this construction to suggest a possible formula for the minimum weight of the dual p -ary code of the desarguesian plane of order pmfor any prime p and any m ≥ 1. [Copyright &y& Elsevier]

A one-dimensional hybrid simulation model incorporating one of the Zakharov equations for the high-frequency waves and a particle-in-cell (PIC) simulation of the ions is described and applied to ionospheric heating using realistic parameters. Results from the hybrid simulation are compared with a Zakharov simulation that incorporates a phenomenological model of ion damping. Both the hybrid and Zakharov simulations predict the formation of solitonlike waves. The early time behavior of the two simulations is different due to the high noise level in the hybrid simulation, but the late time behavior is quite similar. [ABSTRACT FROM AUTHOR]

Data underlying the findings described in this manuscript may be obtained in accordance with AstraZeneca's data sharing policy described at https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure. Lack of effect of benralizumab on signs and symptoms of moderate-to-severe atopic dermatitis: Results from the phase 2 randomized, double-blind, placebo-controlled HILLIER trial Ninety-six patients (including 26 adolescents) and 98 patients (27 adolescents) were randomized into the benralizumab and placebo groups, respectively. [Extracted from the article]

Background and Purpose: Prostanoid EP2 receptor agonists exhibit several activities including ocular hypotension, tocolysis and anti-inflammatory activity. This report describes the affinity and selectivity of a structurally novel, non-prostanoid EP2 receptor agonist, PGN-9856, and its therapeutic potential.Experimental Approach: The pharmacology of a series of non-prostanoid EP2 receptor agonists was determined according to functional and radioligand binding studies, mostly using human recombinant prostanoid receptor transfectants. The selectivity of PGN-9856, as the preferred compound, was subsequently determined by using a diverse variety of non-prostanoid target proteins. The therapeutic potential of PGN-9856 was addressed by determining its activity in relevant primate cell, tissue and disease models.Key Results: PGN-9856 was a selective and high affinity (pKi ≥ 8.3) ligand at human recombinant EP2 receptors. In addition to high affinity binding, it was a potent and full EP2 receptor agonist with a high level of selectivity at EP1 , EP3 , EP4 , DP, FP, IP and TP receptors. In cells overexpressing human recombinant EP2 receptors, PGN-9856 displayed a potency (pEC50 ≥ 8.5) and a maximal response (increase in cAMP) comparable to that of the endogenous agonist PGE2 . PGN-9856 exhibited no appreciable affinity (up 10 μM) for a range of 53 other receptors, ion channels and enzymes. Finally, PGN-9856 exhibited tocolytic, anti-inflammatory and long-acting ocular hypotensive properties consistent with its potent EP2 receptor agonist properties.Conclusions and Implications: PGN-9856 is a potent, selective and efficacious prostanoid EP2 receptor agonist with diverse potential therapeutic applications: tocolytic, anti-inflammatory and notably anti-glaucoma. [ABSTRACT FROM AUTHOR]

Background and Purpose: Preclinical pharmacological characterization of GSK1004723, a novel, dual histamine H(1) and H(3) receptor antagonist.Experimental Approach: GSK1004723 was characterized in vitro and in vivo using methods that included radioligand binding, intracellular calcium mobilization, cAMP production, GTPγS binding, superfused human bronchus and guinea pig whole body plethysmography.Key Results: In cell membranes over-expressing human recombinant H(1) and H(3) receptors, GSK1004723 displayed high affinity, competitive binding (H(1) pKi = 10.2; H(3) pKi = 10.6). In addition, GSK1004723 demonstrated slow dissociation from both receptors with a t(1/2) of 1.2 and 1.5 h for H(1) and H(3) respectively. GSK1004723 specifically antagonized H(1) receptor mediated increases in intracellular calcium and H(3) receptor mediated increases in GTPγS binding. The antagonism exerted was retained after cell washing, consistent with slow dissociation from H(1) and H(3) receptors. Duration of action was further evaluated using superfused human bronchus preparations. GSK1004723 (100 nmol·L(-1) ) reversed an established contractile response to histamine. When GSK1004723 was removed from the perfusate, only 20% recovery of the histamine response was observed over 10 h. Moreover, 21 h post-exposure to GSK1004723 there remained almost complete antagonism of responses to histamine. In vivo pharmacology was studied in conscious guinea pigs in which nasal congestion induced by intranasal histamine was measured indirectly (plethysmography). GSK1004723 (0.1 and 1 mg·mL(-1) intranasal) antagonized the histamine-induced response with a duration of up to 72 h.Conclusions and Implications: GSK1004723 is a potent and selective histamine H(1) and H(3) receptor antagonist with a long duration of action and represents a potential novel therapy for allergic rhinitis. [ABSTRACT FROM AUTHOR]

Vegetation albedo is a critical component of the Earth's climate system, yet efforts to evaluate and improve albedo parameterizations in climate models have lagged relative to other aspects of model development. Here, we calculated growing season albedos for deciduous and evergreen forests, crops, and grasslands based on over 40 site-years of data from the AmeriFlux network and compared them with estimates presently used in the land surface formulations of a variety of climate models. Generally, the albedo estimates used in land surface models agreed well with this data compilation. However, a variety of models using fixed seasonal estimates of albedo overestimated the growing season albedo of northerly evergreen trees. In contrast, climate models that rely on a common two-stream albedo submodel provided accurate predictions of boreal needle-leaf evergreen albedo but overestimated grassland albedos. Inverse analysis showed that parameters of the two-stream model were highly correlated. Consistent with recent observations based on remotely sensed albedo, the AmeriFlux dataset demonstrated a tight linear relationship between canopy albedo and foliage nitrogen concentration (for forest vegetation: albedo=0.01+0.071%N, r2=0.91; forests, grassland, and maize: albedo=0.02+0.067%N, r2=0.80). However, this relationship saturated at the higher nitrogen concentrations displayed by soybean foliage. We developed similar relationships between a foliar parameter used in the two-stream albedo model and foliage nitrogen concentration. These nitrogen-based relationships can serve as the basis for a new approach to land surface albedo modeling that simplifies albedo estimation while providing a link to other important ecosystem processes. [ABSTRACT FROM AUTHOR]

Background and Purpose: Prostanoid EP(4) receptor antagonists may have therapeutic utility in the treatment of migraine since EP(4) receptors have been shown to be involved in prostaglandin (PG)E(2)-induced cerebral vascular dilatation, which may be an important contributor to migraine pain. This study reports the pharmacological characterization of BGC20-1531, a novel EP(4) receptor antagonist.Experimental Approach: BGC20-1531 was characterized in radioligand binding and in vitro functional assays employing recombinant and native EP(4) receptors. Changes in canine carotid haemodynamics were used to assess the pharmacodynamic profile of BGC20-1531 in vivo.Key Results: BGC20-1531 exhibited high affinity at recombinant human EP(4) receptors expressed in cell lines (pK(B) 7.6) and native EP(4) receptors in human cerebral and meningeal artery (pK(B) 7.6-7.8) but showed no appreciable affinity at a wide range of other receptors (including other prostanoid receptors), channels, transporters and enzymes (pKi < 5). BGC20-1531 competitively antagonized PGE(2)-induced vasodilatation of human middle cerebral (pK(B) 7.8) and meningeal (pK(B) 7.6) arteries in vitro, but had no effect on responses induced by PGE(2) on coronary, pulmonary or renal arteries in vitro. BGC20-1531 (1-10 mg.kg(-1) i.v.) caused a dose-dependent antagonism of the PGE(2)-induced increase in canine carotid blood flow in vivo.Conclusions and Implications: BGC20-1531 is a potent and selective antagonist at EP(4) receptors in vitro and in vivo, with the potential to alleviate the symptoms of migraine that result from cerebral vasodilatation. BGC20-1531 is currently in clinical development for the treatment of migraine headache. [ABSTRACT FROM AUTHOR]

Glucocorticoids, the adrenal steroids released during stress, compromise the ability of neurons to survive neurological injury. In contrast, estrogen protects neurons against such injuries. We designed three genetic interventions to manipulate the actions of glucocorticoids, which reduced their deleterious effects in both in vitro and in vivo rat models. The most effective of these interventions created a chimeric receptor combining the ligand-binding domain of the glucocorticoid receptor and the DNA-binding domain of the estrogen receptor. Expression of this chimeric receptor reduced hippocampal lesion size after neurological damage by 63% and reversed the outcome of the stress response by rendering glucocorticoids protective rather than destructive. Our findings elucidate three principal steps in the neuronal stress-response pathway, all of which are amenable to therapeutic intervention. [ABSTRACT FROM AUTHOR]

Previous studies have shown that α-adrenergic activation reduces myocardial damages caused by ischemia/reperfusion. However, the molecular mechanisms of how α-adrenergic activation protects the myocardium are not completely understood. The objective of this study was to test the hypothesis that α-adrenergic activation protects the myocardium by, at least in part, inhibiting apoptosis in cardiomyocytes. The current data has shown that apoptosis in neonatal rat cardiomyocytes, induced by 24 h treatment with hypoxia (95% N[sub 2] and 5% CO[sub 2]) and serum deprivation, was inhibited by co-treatment with phenylephrine. Pre-treatment with phenylephrine for 24 h also protected cardiomyocytes against subsequent 24 h treatment with hypoxia and serum deprivation. Exposure of cardiomyocytes to phenylephrine for up to 9 days under normoxic conditions did not cause apoptosis. The phenylephrinemediated cytoprotection was blocked by an α-adrenergic antagonist, phentolamine. β-adrenergic activation with isoproterenol did not protect cardiomyocytes against hypoxia and serum deprivation-induced apoptosis. Under hypoxic conditions, phenylephrine prevented the down-regulation of Bcl-2 and Bcl-X mRNA/protein and induced hypertrophic growth. Phenylephrine-mediated protection was abrogated by the phosphatidylinositol 3-kinase (PI 3-kinase) inhibitor wortmannin and was mimicked by the caspase-9 peptidic inhibitor LEHD-fmk. These results suggest that α-adrenergic activation protects cardiomyocytes against hypoxia and serum deprivation-induced apoptosis through regulating the expression of mitochondrion-associated apoptosis regulatory genes, preventing activation of mitochondrial damage-induced apoptosis pathway (cytochrome C-caspase-9), and activating hypertrophic growth. [ABSTRACT FROM AUTHOR]